Is PEX1 p.Arg948Gln (c.2843G>A) pathogenic?

PEX1 p.Arg948Gln (c.2843G>A) is classified Uncertain significance in PEX1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-26). AlphaMissense: likely benign (0.2353); Very rare (popmax 0.00814%, nfe); Associated with Zellweger spectrum disorders.

What condition is associated with PEX1 p.Arg948Gln (c.2843G>A)?

PEX1 p.Arg948Gln (c.2843G>A) is associated with Zellweger spectrum disorders, peroxisome biogenesis disorder 1A (Zellweger), peroxisome biogenesis disorder 1B (ClinVar).

How common is PEX1 p.Arg948Gln (c.2843G>A) in the general population?

PEX1 p.Arg948Gln (c.2843G>A) is very rare (popmax 0.00814%, nfe) (gnomAD).

How is Zellweger syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PEX1 p.Arg948Gln (c.2843G>A)?

AlphaMissense predicts likely benign (score 0.2353) — an in-silico prediction, not a clinical call.

PEX1 p.Arg948Gln

c.2843G>A · rs535271603 · VCV441031

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.2353 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00814%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Zellweger spectrum disorders

Computational evidence

Protein change
AlphaMissense	0.2353	likely benign
REVEL	0.829	moderately pathogenic-leaning
SaProt	LLR -10.23	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 4	GERP 3, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 41 kb · p 4.3e-05 · regional, not allelic
Overall
CADD	27.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00814% European (non-Finnish) · 96/1,179,866 alleles

Filtering AF 0.00681% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00633%

Overall 0.00657% 106/1,613,928 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0169%	5,919
European (non-Finnish)grpmax	0.00814%	12,290
Remaining individualsnot grpmax-eligible	0.0048%	20,835
East Asian	0.00223%	44,878
Admixed American	0.00167%	60,006

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: PEX1
Protein: p.Arg948Gln
Coding: c.2843G>A
MANE Select: NM_021167 · reported on NM_000466
dbSNP: rs535271603
Type: single nucleotide variant
Location: chr7:92494570 (GRCh38)

Full PEX1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Zellweger spectrum disorders — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: peroxisome biogenesis disorder 1A (Zellweger)peroxisome biogenesis disorder 1B

For Zellweger syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/pex1-p-arg948gln (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown